(A) Field of the Invention
The present invention relates to a method for preparing hexose derivatives, and more particularly, to a method for preparing hexose derivatives with highly regioselective scheme to protect individual hydroxyls of monosaccharide units and install an orthogonal protecting group pattern in a one-pot manner.
(B) Description of the Related Art
Carbohydrates are involved in numerous vital life processes. They are structurally diverse and complex as compared to other biopolymers (proteins and nucleic acids) and are present in micro-heterogeneous forms in nature. Chemical synthesis of carbohydrates, the practical route to procure pure oligosaccharides, is however hampered by two major hurdles, regioselective protection of polyhydroxyls and rapid assembly of glycosidic linkages involving the stereoselective control of α- or β-glycosidic bonds.
Oligosaccharides and glycoconjugates play significant roles in a diverse set of biological processes, including viral and bacterial infections, cell growth and proliferation, cell-cell communication, as well as immuno-response. Their structural diversity, which allows them to encode information required for specific molecular recognition, and determine the posttranscriptional modification of proteins, is much more complex than that of proteins and nucleic acids. As most of the structural information of carbohydrate-protein, carbohydrate-nucleotide, and carbohydrate-carbohydrate complex at molecular level remains obscure, homogeneous materials with well-defined configurations are essential for the determination of biological function and structure-activity relationship (SAR). However, these oligosaccharides being present in micro-heterogeneous forms cannot be procured easily from natural sources in acceptable purity and amounts. Chemical methods to synthesize these function-oriented domains have therefore acquired immense importance.
In comparison with other biopolymers, peptides/proteins and nucleotides/DNA and RNA, the preparation of oligosaccharides is obviously more difficult since no regio- and stereochemical issues are involved in the sequential coupling steps for the construction of amide or phosphate bonds, respectively. The biggest challenge in carbohydrate synthesis is not only the rapid assembly of oligosaccharides involving the stereoselective control of α- or β-glycosidic bonds, but also the preparation of selectively protected monosaccharide units, one with a strategically positioned free hydroxy group (a nucleophilic acceptor) and one bearing a labile leaving group at the anomeric carbon that acts as a glycosyl donor in the ensuing glycosylation reaction. Along with this, the installation of suitable protecting groups on the remaining hydroxyls, for tuning the overall electronic properties of donors and acceptors so as to “match” the donor-acceptor pair and also for further deprotection and glycosylation or functional group modifications, is required.
FIG. 1 illustrates a traditional chemical approach for carbohydrate synthesis involving protection and glycosylation. A hexose 1 is well-known to be protected easily at the anomeric carbon (C1) to furnish the corresponding hexopyranoside 2 via the formation of cyclic acetal. Transformation of hexopyranoside 2 into either the fully protected monosaccharide 3 or the individual alcohols 4 with a free hydroxyl at C2, C3, C4, or C6 frequently encounters several difficulties, such as (1) an independent and multi-step protection-deprotection sequence is needed to prepare each compound (4-6 steps), (2) a tedious workup is often used in each synthetic step, (3) a time-consuming purification is required to separate different regioisomers, and (4) low yield of the expected product is sometimes obtained due to the poor regioselectivity.
FIG. 2(a) and FIG. 2(b) illustrate traditional chemical approaches for synthesizing the target oligosaccharides from the building blocks. Once the basic building blocks are constructed, the target oligosaccharide can be stereoselectively assembled either from the non-reducing end (FIG. 2(a)) or from the reducing end (FIG. 2(b)) of the starting sugar unit. Referring to FIG. 2A, the anomeric protecting group of a fully protected monosaccharide 3 has to be converted into a labile leaving group (LG) to yield the glycosyl donor 5. This leaving group is then chemo-selectively activated using a promoter system to liberate the anomeric function and the so-formed reactive sugar intermediate is concomitantly coupled with the glycosyl acceptor 4 to give the disaccharide 6. A stepwise iteration of this protocol leads to the trisaccharide 7 and the process can be repeated to provide the higher oligosaccharides. In the alternative protocol (FIG. 2(b)), the anomeric center of compound 5 is first blocked by a conjugate group, depending on the purpose of target molecule, to obtain the reducing end saccharide 8.
The subsequent step demands selective removal of one of the protecting groups to generate the corresponding alcohol that is similarly employed in the coupling step with 15, aided by the promoter, to get the disaccharide 9. Repetition of this deprotection-glycosylation sequence provides the trisaccharide 10 and higher oligomers.